Fuzionaire Diagnostics can add Si–18F radiolabels to a variety of molecules quickly, easily and cheaply

Several years ago, Anton Toutov was a graduate student at the California Institute of Technology, US, working in the lab of Nobel prize-winning chemist Robert Grubbs. He and a colleague discovered they could make carbon–silicon bonds with a safe and inexpensive potassium catalyst. This ability to make silicon-containing organic molecules without using rare and expensive precious metal catalysts is the basis for a new spin-out company, Fuzionaire Diagnostics, based in California.

The firm’s initial goal is to use potassium catalysis to make positron emission tomography (PET) radiotracers that can diagnose and image a wide variety of diseases, and accelerate drug discovery. ‘This application is not just an idea: we actually have the most compelling chemistry data that’s ever been observed in the industry for that application, and now we’re on to validating the biology,’ says Toutov.

By far the most widely-used positron emitter in PET imaging is fluorine-18. However, as F-18’s half-life is just under two hours, it needs to be introduced into tracer molecules as late and as fast as possible before being administered. Time is of the essence during the radiolabelling step and final purification.

Fuzionaire’s strategy revolves around generating tracers with a silicon–fluorine bond, using non-radioactive fluorine-19 initially, and then exchanging that F-19 for radioactive F-18. The isotope exchange is done using F-18 derived from a cyclotron, which Toutov says is ‘the ideal clinical source’.

Scheme showing attachment of silicon fluoride unit to the molecule, followed by exchange for F-18

Source: © Fuzionaire Dx

Fuzionaire uses potassium catalysis to add Si-F tags to a variety of heterocycles, then exchanges the F-19 for positron-emitting F-18

The technology builds on work from several other groups developing organosilicon fluoride radiotracers, including David Perrin from the University of British Columbia in Vancouver, Canada, and Ralf Schirrmacher from the University of Alberta in Edmonton, Canada, whose research focuses on developing new PET imaging agents for use in oncology and neurology. Schirrmacher notes that Fuzionaire’s technology closely resembles his team’s silicon fluoride acceptors chemistry that rely on isotopic exchange to introduce the F-18 label.

Toutov acknowledges these pioneers for their work demonstrating the value of using organosilicon molecules in PET. He goes on to explain that Fuzionaire’s process has two major advantages – the potassium catalysis allows the team to silylate (and then fluorinate) C–H bonds on a wide variety of heterocycles very easily. ‘That means we can rapidly create libraries of molecules with very specific stereoelectronic environments around the silicon atom,’ he says. In turn, that can enhance the kinetics and efficiency of the radiolabelling isotope exchange step, he adds.

Fuzionaire’s advisory board includes the inventor of PET imaging, Mike Phelps, who is a personal friend of Grubbs. ‘When Bob saw how this chemistry was developing, he made the immediate connection that it could be applied to radiochemistry,’ Toutov recalls.

Scheme showing the process for attaching F-18 probes to molecules that target specific areas of the body

Source: © Fuzionaire Dx

The heterocycle Si-F tags can easily be attached to molecules that target specific areas in the body

Grubbs recognised that one of the big limitations in PET is the difficulty of incorporating F-18 into molecules. ‘If we can do that as well as we want, then we can turn anything into a radiolabel compound, and that would be enormously enabling,’ Toutov remarks.

Peter Scott, who directs PET chemistry at the University of Michigan in Ann Arbor, US, describes Fuzionaire and its technology as ‘an interesting new example of how to incorporate F-18 into a bioactive molecule.’

Although Scott applauds the development of new technologies for synthesis of PET radiopharmaceuticals, he notes that the hurdles to their validation, regulatory approval and widespread use remain ‘enormous challenges.’ Scott also notes that these Fuzionaire developments are similar to work with silicon–fluorine and boron–fluorine bonds coming from other research groups.

Meanwhile, Fuzionaire has some initial in vivo trials with small animals underway at a leading US research institution. The company is also in talks with several imaging centres and research institutions across the country about how they might use its technology to treat traditionally challenging diseases in areas like neurology and oncology.